Accelerated MEN2A in homozygous RET carriers in the context of consanguinity.

Background: Homozygous mutations, 2 identical gene versions (alleles), 1 from each biological parent, are exceptional. Clinical descriptions of affected families, comprising few carriers only, are scattered throughout the literature, hindering evidence generation.

Methods: Included in this literature analysis were 5 RET families with ≥1 homozygous carrier and ≥3 heterozygous carriers per family.

Results: In consanguineous families with first-degree cousins, homozygotes presented with node-positive medullary thyroid cancer and pheochromocytoma in their mid-teens, whereas heterozygotes presented in their end-30s and early 40s. Homozygotes developed node-positive medullary thyroid cancer 27.4 years and pheochromocytoma 23 years earlier than heterozygotes. These age differences were smaller in the 15 families carrying founder mutation p.Leu666delinsAsnSer, whereas homozygotes developed node-positive medullary thyroid cancer in their mid-40s, 6 years earlier than heterozygotes in their early 50s.

Conclusion: These results, limited in scope and size and modulated by extent of consanguinity, are consistent with moderate dose-response effects accelerating MEN2A development.